Aminoalkanols of arylacetic acids



Patented Apr. 30, 1946 UNITED STATES PATENT or FICE 2,899,508 AMINOALKANOLS F ARYLACETIC ACIDS John S. Pierce. Richmond, Va.

No Drawing. Application December 8. 1943, Serial No. 513,191

Claims.

This invention relates to certain aminoalkanols oi arylacetic acids. More specifically, it relates to arylacetates of p-methyl-p-monoalkylaminopropanols oi the general structure Cc'HsCH (A) COOCH2C(CHJ) zNHR CsHsCH (A) COOCHzC (CH3) zNHR in which A and R have the significance indicated above. These substances are colorless oils, practically insoluble in water but soluble in ether. Many of these oils form fairly soluble salts with acids, for example, hydrochloric, and are purified conveniently, in many cases, by recrystallization from organic solvents such as acetone or acetone and ether. In some cases, however, the reaction product of the oil and hydrochloric acid is not very soluble in either water or ether and in other cases the hydrochloride oi the oil is practically insoluble in water but i appreciably soluble in ether. These esters are prepared preferably by the reaction of the appropriate acyl halide and B-monoalkylamino-p-methylpropanol, the latter usually and preferably being present as the hydrochloride.

The following examples serve to illustrate the invention but do not limit it in any way.

EXAMPLE I To 290 parts by weight of 2-methyl-2-monon-butylamino-l-propanol was added 250 parts by weight of concentrated hydrochloric acid. The excess hydrochloric acid and the water were removed by vacuum evaporation. 300 parts by weight of phenylacetyl chloride was added. Appreciable hydrogen chloride was evolved. The

dilute hydrochloric acid and the aqueous acid solution was treated with excess-sodium hydroxide solution. The oil which came out of solution was extracted with isopropyl ether. Dry hydrogen chloride was passed into the isopropyl ether. The product, p-methyi-p-mono-n-butylaminopropyl phenylacetate hydrochloride, came down as an oil. The isopropyl ether was decanted from the oil and the product was recrystallized from dry acetone. See Table II for melting point and analysis.)

EXAMPLE II A mixture of 255 parts by weight of 2-methyl- 2-mono-n-hexylamino-l-propanol and 146 parts by weight of phenylethylacetyl chloride was heated on an oil bath at 105 C. for one hour. The reaction mixture was dissolved in alcohol and poured into dilute sodium hydroxide solution. The oily insoluble layer was extracted with ether. The ether solution was shaken with N hydrochloric acid but the amino alcohol ester remained largely in the ether solution instead of going in the aqueous acid layer, as in some other cases.

lamylamino-propanol hydrochloride and diphenmixture was heated on a water bath ior 4 hours and finally gently with a free flame for about one minute. There was a slight evolution of hydrogen chloride on this last heating. The reaction mixture was dissolved in about two vol umes of alcohol and was poured into a large excess of dilute sodium hydroxide solution. The oil which came out of solution was extracted with ether. The ether solution was extracted with analysis.)

The ether solution was evaporated and the oily residue was stirred with hydrochloric acid. On standing for a short time, solidification took place. The product, flemethyl-fl-mono-n-hexyiaminopropyl phenylethylacetate hydrochloride, was recrystallized (and to some extent, thrown out of solution) from anhydrous acetone and dry ether. (See Table II for melting point and EXAMPLE III Equimolar quantities of p-methyl-p-mono-nylacetyl chloride were heated on an oil bath at for 30 minutes and at for 5 minutes.

i The reaction product was dissolved in a small volume of alcohol and was poured into a large excess of dilute sodium hydroxide solution. Isopropyl ether was used to extract the oily layer. The isopropyl ether was shaken with dilute sodium hydroxide solution to remove any traces of diphenylacetic acid. Next, it was treated with dilute hydrochloric acid. Some amino alcohol ester dissolved in the acid solution. Some came out of solution as an oil. This oil apparently was the hydrochloride of s-methyl-p-mono-n-amylaminopropyl diphenylacetate. for a sample of it crystallized readily when seeded with the above product. The remainder of the oil and the acid solution were made basic with sodium hydroxide solution and extracted with isopropyl ether. The

CsH5CH(A) COOCHQCXYNHR In the compounds prepared, A, X, Y and R. were varied as indicated below in Table I. For convenience and for brevity in this report. variationsin R are noted as certain combinations of A, x and Y remain unchanged.

For convenience, the arylacetates of the monoalkylaminoalkanols listed in this application usually were isolated as the hydrochlorides. The hydrochlorides were obtained as oils, usually by the addition of hydrogen chloride to an isopropyl ether solution of the free base of the amino alcohol ester. In most cases the oils were not converted to solids but in some cases it was possible to isolate crystalline products. This was particularly true of the hydrochlorides of the ,fi-methylfl-monoalkylaminopropyl arylacetates. In a pharmaceutical product, purity is a matter of the utmost importance. Therefore, even though some of the above derivatives of aminoalkanols other than p-methyl-p-monoalkylaminopropanols have appreciable antispasmodic activity, they are not included in this application.

Table II contains most of the p-methyl-pmonoalkylaminopropyl arylacetate hydrochlorides which were obtained in a satisfactory crystalline state for melting point determinations and for analyses. Some of these products were crystallized with great dimculty, so it is quite likely that other monoalkylaminoalkyl arylacetate hydrochlorides, by proper treatment with the right solvent, could be converted to crystalline solids. For preliminary tests on isolated intestine, however, solutions of the oil or gummy solids served satisfactorily.

p-Methyl-p-monoalkylammomml phenvlacctatc, diphenylacetate and phenylalkylacetate hydrochloride:

C.H;OH(A)OOOOHQOwHOaNHILHCl l Anslysis A R Molm pe cent 1 iormula (um Oslod. Found H n-CsHr. CuHuOsNCL... 112-113 12.41 12.61 H. 11-01310.--- CiaHssOsN O 1%127 11.83 12.00 Cells-n. n-OrH1.. 158-160 9.80 0.78 Cane-u. n-OeHs--- CIHIOIB C 173-174 9.43 9.44 OsHL-n n-Cs u-.- OIHIOINC 117-118 9.09 9.0! OaH n-Odiu.-. CaHleOsNC -101 8.78 8.76 loo-C 35.031 0 166-107 9.43 9.44 C inc-Clan Gums 141-142 9.09 0.12 O;E.g.... n-CsHr... OuHsIOshO lib-116 11.00 11.46 0mi n-(leflu-n 0 109-110 10.81 10.00 01H..-- n-0Hu CnKaOINCL..- -120 9.90 10. 21

1 The melting points given in Table II are for identification purpolal only, and do not limit the application in any way.

One of the most popular methods of testing the value of an antispasmodic is on the isolated segment of the small intestine, immersed in oxygenated Locke's, Tyrode or some similar solution. Observations were made of the eflect on normal muscle tonus or contractions or the influence of the agent on spasms induced by (a) acetyl choline, which acts through the nerve supply, or (b) barium chloride or morphine sulfate, which acts directly on the muscle.

Some of the arylacetates oi p-methyl-p-monoalkylaminopropanols covered by this application far surpass atropine as an antispasmodic agent, as shown by certain tests on the isolated segment of the small intestine. Tracings were taken with the hydrochloride of p-methyl-p-mono-nhexylaminopropyl a-phenylbutyrate CdIrCHCOOCHsC (CHshNHCHzCHsCHsCHzCHzCHr-HCI listed as A for brevity in the following discussion.

On the isolated intestine of the rabbit or cat (jejunum), the solution of "A," l:100,000, caused a marked decrease in the tone of the previously undrugged longitudinal muscle. In most instances this was accompanied by cessation of the rhythmic contractions of the segment. In some instances, although the reduction in tone took place, rhythmic contractions continued. The effect of 1:200,000 solution of A was similar, but much less pronounced. It was enerally possible to restore tonicity and rhythmic contractions of the segment by washing with plain Locke's solution.

Surrounding the segment of intestine by 1:500,000 solution of acetylcholine bromide and 1:100,000 solution of A" resulted in a marked spasm of the muscle, with a rapid recovery and return to the preexisting tone-level or to a lower one. This was in marked contrast to the behavior of the segment subjected to the influence of 1:500,000 acetylcholine bromide alone-here, the spasm persisted for a considerable time.

When increased tone of the muscle was induced by morphine sulfate, 1:50.000, this was relieved promptly by substituting a solution of A," 1:100,000 in morphine sulfate, 1:50.000.

The spasm induced by bathing the segment in barium chloride, 1:50.000, was relieved promptly by substituting a solution of A," 1:100,000 barium chloride, 1:50.000.

One objectionable feature of atropine as an antispasmodic is its eflect on salivary secretion. A dose or 0.5 mg. of atropine causes some dryness of the mouth and throat and a dose of 5.0 mg. causes one to have difllculty in swallowing (The Pharmacological Basis of Therapeutics, p. 170, 1941 edition, by Goodman and Gilman. Publisher, The Macmillan Company, New York city). In tests carried out with A, rabbits were injected with 10 mg. of pilocarpine hydrochloride per kilogram, causing excessive salivary secretion. The injection of 5 mg. or A per kilogram intravenously had no effect on the'flow of saliva.

The eflect of 1 100,000 solution of another antispasmodic, s-methyl-p-mono-n-butylaminopropyl u-phenylbutyrate hydrochloride, on the isolated intestinal segment of the rabbit was reduction in rhythmic contractions and decrease in tone. This seemed reversible, contractions being resumed and a return to previous. tone-level being produced by washing with Locke's solution. Also, the tone of the isolated intestine of the chicken was reduced markedly by 1:100,000 solution of this antispasmodic.

I claim:

1. As new products, compounds of the structure cimcma) COOCH3C(CH3) mm in which A is a member of the group hydrogen,

phenyl and alhl of from two to six carbons and R is. a primary alkyl radical of from two to six carbons, and salts thereof.

2. As new products, compounds of the structure CsHsCI-I(A) COOCHzC(CHa) QNI'IR COH OHCOO CHQO (CH1):NHCHsOHaGHaOHaCHgCH:

and salts thereof.

4. As a new compound,

CcH CHO O O CHgO (CHahNHCHaCHgOHgCH:

and salts thereof.

5. As a new compound cano'moooomc(crmmncmomcmomon.

u and salts thereof.

JOHN S. PERCE. 

